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1.  Obtaining informed consent for genomics research in Africa: analysis of H3Africa consent documents 
Journal of Medical Ethics  2015;42(2):132-137.
The rise in genomic and biobanking research worldwide has led to the development of different informed consent models for use in such research. This study analyses consent documents used by investigators in the H3Africa (Human Heredity and Health in Africa) Consortium.
A qualitative method for text analysis was used to analyse consent documents used in the collection of samples and data in H3Africa projects. Thematic domains included type of consent model, explanations of genetics/genomics, data sharing and feedback of test results.
Informed consent documents for 13 of the 19 H3Africa projects were analysed. Seven projects used broad consent, five projects used tiered consent and one used specific consent. Genetics was mostly explained in terms of inherited characteristics, heredity and health, genes and disease causation, or disease susceptibility. Only one project made provisions for the feedback of individual genetic results.
H3Africa research makes use of three consent models—specific, tiered and broad consent. We outlined different strategies used by H3Africa investigators to explain concepts in genomics to potential research participants. To further ensure that the decision to participate in genomic research is informed and meaningful, we recommend that innovative approaches to the informed consent process be developed, preferably in consultation with research participants, research ethics committees and researchers in Africa.
PMCID: PMC4752624  PMID: 26644426
Informed Consent
2.  Cost-Effectiveness of a National Initiative to Improve Hand Hygiene Compliance Using the Outcome of Healthcare Associated Staphylococcus aureus Bacteraemia 
PLoS ONE  2016;11(2):e0148190.
The objective is to estimate the incremental cost-effectiveness of the Australian National Hand Hygiene Inititiave implemented between 2009 and 2012 using healthcare associated Staphylococcus aureus bacteraemia as the outcome. Baseline comparators are the eight existing state and territory hand hygiene programmes. The setting is the Australian public healthcare system and 1,294,656 admissions from the 50 largest Australian hospitals are included.
The design is a cost-effectiveness modelling study using a before and after quasi-experimental design. The primary outcome is cost per life year saved from reduced cases of healthcare associated Staphylococcus aureus bacteraemia, with cost estimated by the annual on-going maintenance costs less the costs saved from fewer infections. Data were harvested from existing sources or were collected prospectively and the time horizon for the model was 12 months, 2011–2012.
No useable pre-implementation Staphylococcus aureus bacteraemia data were made available from the 11 study hospitals in Victoria or the single hospital in Northern Territory leaving 38 hospitals among six states and territories available for cost-effectiveness analyses. Total annual costs increased by $2,851,475 for a return of 96 years of life giving an incremental cost-effectiveness ratio (ICER) of $29,700 per life year gained. Probabilistic sensitivity analysis revealed a 100% chance the initiative was cost effective in the Australian Capital Territory and Queensland, with ICERs of $1,030 and $8,988 respectively. There was an 81% chance it was cost effective in New South Wales with an ICER of $33,353, a 26% chance for South Australia with an ICER of $64,729 and a 1% chance for Tasmania and Western Australia. The 12 hospitals in Victoria and the Northern Territory incur annual on-going maintenance costs of $1.51M; no information was available to describe cost savings or health benefits.
The Australian National Hand Hygiene Initiative was cost-effective against an Australian threshold of $42,000 per life year gained. The return on investment varied among the states and territories of Australia.
PMCID: PMC4747462  PMID: 26859688
3.  Exploring researchers’ experiences of working with a researcher-driven, population-specific community advisory board in a South African schizophrenia genomics study 
BMC Medical Ethics  2015;16:45.
Community engagement within biomedical research is broadly defined as a collaborative relationship between a research team and a group of individuals targeted for research. A Community Advisory Board (CAB) is one mechanism of engaging the community. Within genomics research CABs may be particularly relevant due to the potential implications of research findings drawn from individual participants on the larger communities they represent. Within such research, CABs seek to meet instrumental goals such as protecting research participants and their community from research-related risks, as well as intrinsic goals such as promoting the respect of participants and their community. However, successful community engagement depends on the degree to which CABs legitimately represent and engage with communities targeted for research. Currently, there is little literature describing the use of CABs in genomics research taking place in developing countries, and even less in the field of genomics research relating to mental illness. The aim of this article is to describe and consider the contributions made by a researcher-driven, population-specific CAB in a genomics of schizophrenia research project taking place in South Africa, from the perspective of the research team.
Four broad discussion topics emerged during the CAB meetings namely: 1) informed consent procedures, 2) recruitment strategies, 3) patient illness beliefs and stigma experiences, and 4) specific ethical concerns relating to the project. The authors consider these discussions in terms of their contributions to instrumental and intrinsic goals of community engagement.
The CAB gave valuable input on the consent processes and materials, recruitment strategies and suggested ways of minimizing the potential for stigma and discrimination. All of these contributions were of an instrumental nature, and helped improve the way in which the research took place. In addition, and perhaps more importantly, the CAB made a unique and important contribution relating to intrinsic functions such as promoting the respect and dignity of research participants and their community. This was particularly evident in ensuring sensitivity and respect of the community’s traditional beliefs about schizophrenia and its treatment, and in this way promoting a respectful relationship between the research team and the participants.
PMCID: PMC4487967  PMID: 26135122
Community engagement; Genomics research; Community advisory board; Schizophrenia; Xhosa
4.  Community engagement strategies for genomic studies in Africa: a review of the literature 
BMC Medical Ethics  2015;16:24.
Community engagement has been recognised as an important aspect of the ethical conduct of biomedical research, especially when research is focused on ethnically or culturally distinct populations. While this is a generally accepted tenet of biomedical research, it is unclear what components are necessary for effective community engagement, particularly in the context of genomic research in Africa.
We conducted a review of the published literature to identify the community engagement strategies that can support the successful implementation of genomic studies in Africa. Our search strategy involved using online databases, Pubmed (National Library of Medicine), Medline and Google scholar. Search terms included a combination of the following: community engagement, community advisory boards, community consultation, community participation, effectiveness, genetic and genomic research, Africa, developing countries.
A total of 44 articles and 1 thesis were retrieved of which 38 met the selection criteria. Of these, 21 were primary studies on community engagement, while the rest were secondary reports on community engagement efforts in biomedical research studies. 34 related to biomedical research generally, while 4 were specific to genetic and genomic research in Africa.
We concluded that there were several community engagement strategies that could support genomic studies in Africa. While many of the strategies could support the early stages of a research project such as the recruitment of research participants, further research is needed to identify effective strategies to engage research participants and their communities beyond the participant recruitment stage. Research is also needed to address how the views of local communities should be incorporated into future uses of human biological samples. Finally, studies evaluating the impact of CE on genetic research are lacking. Systematic evaluation of CE strategies is essential to determine the most effective models of CE for genetic and genomic research conducted in African settings.
PMCID: PMC4407431  PMID: 25889051
Community engagement; Genetics; Genomic research; Africa
5.  A library of MiMICs allows tagging of genes and reversible, spatial and temporal knockdown of proteins in Drosophila 
eLife  null;4:e05338.
Here, we document a collection of ∼7434 MiMIC (Minos Mediated Integration Cassette) insertions of which 2854 are inserted in coding introns. They allowed us to create a library of 400 GFP-tagged genes. We show that 72% of internally tagged proteins are functional, and that more than 90% can be imaged in unfixed tissues. Moreover, the tagged mRNAs can be knocked down by RNAi against GFP (iGFPi), and the tagged proteins can be efficiently knocked down by deGradFP technology. The phenotypes associated with RNA and protein knockdown typically correspond to severe loss of function or null mutant phenotypes. Finally, we demonstrate reversible, spatial, and temporal knockdown of tagged proteins in larvae and adult flies. This new strategy and collection of strains allows unprecedented in vivo manipulations in flies for many genes. These strategies will likely extend to vertebrates.
eLife digest
In the last few decades, technical advances in altering the genes of organisms have led to many discoveries about how genes work. For example, it is now possible to add a specific DNA sequence to a gene so that the protein it makes will carry a ‘tag’ that enables us to track it in cells. One such tag is called green fluorescent protein (GFP) and it is often used to study other proteins in living cells because it produces green fluorescence that can be detected under a microscope.
It is labor intensive to add tags to individual genes, so this limits the number of proteins that can be studied in this way. In 2011, researchers developed a new method that can easily tag many genes in fruit flies. It makes use of small sections of DNA called transposons, which are able to move around the genome by ‘cutting’ themselves out of one location and ‘pasting’ themselves in somewhere else.
The researchers used a transposon called Minos, which is naturally found in fruit flies. When Minos inserts into a gene, it often disrupts the gene and stops it from working. However, the researchers could swap the inserted transposon for a gene encoding GFP by making use of a natural process that rearranges DNA in cells. This resulted in the protein encoded by the gene containing GFP and so it can be detected under a microscope. This method allowed the researchers to create a collection of fly lines that have the GFP tag on many different proteins.
Now, Nagarkar-Jaiswal et al. have greatly expanded this initial collection. More than 75% of GFP-tagged proteins worked normally and the flies producing these altered proteins remain healthy. It is possible to use a technique called RNA interference against the GFP to lower the production of the tagged proteins. Moreover, Nagarkar-Jaiswal et al. show that it is also possible to degrade the tagged proteins so that less protein is present. The removal of proteins is reversible and can be done in specific tissues during any phase in fly development. These techniques allow researchers to directly associate the loss of the protein with the consequences for the fly.
This collection of fruit fly lines is a useful resource that can help us understand how genes work. The method for tagging the proteins could also be modified to work in other animals.
PMCID: PMC4379497  PMID: 25824290
RMCE; deGradFP; iGFPi; bruchpilot; discs large 1; dunce; D. melanogaster
6.  Using a theory of planned behaviour framework to explore hand hygiene beliefs at the ‘5 critical moments’ among Australian hospital-based nurses 
Improving hand hygiene among health care workers (HCWs) is the single most effective intervention to reduce health care associated infections in hospitals. Understanding the cognitive determinants of hand hygiene decisions for HCWs with the greatest patient contact (nurses) is essential to improve compliance. The aim of this study was to explore hospital-based nurses’ beliefs associated with performing hand hygiene guided by the World Health Organization’s (WHO) 5 critical moments. Using the belief-base framework of the Theory of Planned Behaviour, we examined attitudinal, normative, and control beliefs underpinning nurses’ decisions to perform hand hygiene according to the recently implemented national guidelines.
Thematic content analysis of qualitative data from focus group discussions with hospital-based registered nurses from 5 wards across 3 hospitals in Queensland, Australia.
Important advantages (protection of patient and self), disadvantages (time, hand damage), referents (supportive: patients, colleagues; unsupportive: some doctors), barriers (being too busy, emergency situations), and facilitators (accessibility of sinks/products, training, reminders) were identified. There was some equivocation regarding the relative importance of hand washing following contact with patient surroundings.
The belief base of the theory of planned behaviour provided a useful framework to explore systematically the underlying beliefs of nurses’ hand hygiene decisions according to the 5 critical moments, allowing comparisons with previous belief studies. A commitment to improve nurses’ hand hygiene practice across the 5 moments should focus on individual strategies to combat distraction from other duties, peer-based initiatives to foster a sense of shared responsibility, and management-driven solutions to tackle staffing and resource issues. Hand hygiene following touching a patient’s surroundings continues to be reported as the most neglected opportunity for compliance.
PMCID: PMC4341863  PMID: 25888894
Infection prevention; Health care-associated infections; Nurses; Attitudes; Barriers; Theory of planned behaviour
7.  Streamlined research funding using short proposals and accelerated peer review: an observational study 
Despite the widely recognised importance of sustainable health care systems, health services research remains generally underfunded in Australia. The Australian Centre for Health Services Innovation (AusHSI) is funding health services research in the state of Queensland. AusHSI has developed a streamlined protocol for applying and awarding funding using a short proposal and accelerated peer review.
An observational study of proposals for four health services research funding rounds from May 2012 to November 2013. A short proposal of less than 1,200 words was submitted using a secure web-based portal. The primary outcome measures are: time spent preparing proposals; a simplified scoring of grant proposals (reject, revise or accept for interview) by a scientific review committee; and progressing from submission to funding outcomes within eight weeks. Proposals outside of health services research were deemed ineligible.
There were 228 eligible proposals across 4 funding rounds: from 29% to 79% were shortlisted and 9% to 32% were accepted for interview. Success rates increased from 6% (in 2012) to 16% (in 2013) of eligible proposals. Applicants were notified of the outcomes within two weeks from the interview; which was a maximum of eight weeks after the submission deadline. Applicants spent 7 days on average preparing their proposal. Applicants with a ranking of reject or revise received written feedback and suggested improvements for their proposals, and resubmissions composed one third of the 2013 rounds.
The AusHSI funding scheme is a streamlined application process that has simplified the process of allocating health services research funding for both applicants and peer reviewers. The AusHSI process has minimised the time from submission to notification of funding outcomes.
PMCID: PMC4324047  PMID: 25888975
8.  Differential involvement of p38 and JNK MAP kinases in HIV-1 Tat and gp120-induced apoptosis and neurite degeneration in striatal neurons 
Neuroscience  2005;135(3):781-790.
The role of p38 and c-jun-N-terminal kinases 1/2 (JNK), members of the mitogen-activated protein kinase (MAPK) family, in mediating the toxic effects of HIV-1 Tat and gp120 were explored in primary mouse striatal neurons in vitro. Both Tat and gp120 caused significant increases in p38 and JNK MAPK phosphorylation, caspase-3 activity, neurite losses and cell death in striatal neurons. Tat-induced increases in caspase-3 activity were significantly attenuated by an inhibitor of JNK (SP600125), but not by an inhibitor of p38 (SB203580), MAPK. However, despite preventing increases in caspase-3 activity, JNK inhibition failed to avert Tat-induced neuronal losses suggesting that the reductions in caspase-3 activity were insufficient to prevent cell death caused by Tat. Alternatively, gp120-induced increases in caspase-3 activity, neurite losses and neuronal death were prevented by p38, but not JNK, MAPK inhibition. Our findings suggest that gp120 induces neuronal dysfunction and death through actions at p38 MAPK, while Tat kills neurons through actions that are independent of p38 or JNK MAPK, or through the concurrent activation of multiple proapoptotic pathways.
PMCID: PMC4310730  PMID: 16111829
Caspase-3; neurotoxicity; AIDS; neurodegeneration; basal ganglia
9.  Basal ganglia and cortical networks for sequential ordering and rhythm of complex movements 
Voluntary actions require the concurrent engagement and coordinated control of complex temporal (e.g., rhythm) and ordinal motor processes. Using high-resolution functional magnetic resonance imaging (fMRI) and multi-voxel pattern analysis (MVPA), we sought to determine the degree to which these complex motor processes are dissociable in basal ganglia and cortical networks. We employed three different finger-tapping tasks that differed in the demand on the sequential temporal rhythm or sequential ordering of submovements. Our results demonstrate that sequential rhythm and sequential order tasks were partially dissociable based on activation differences. The sequential rhythm task activated a widespread network centered around the supplementary motor area (SMA) and basal-ganglia regions including the dorsomedial putamen and caudate nucleus, while the sequential order task preferentially activated a fronto-parietal network. There was also extensive overlap between sequential rhythm and sequential order tasks, with both tasks commonly activating bilateral premotor, supplementary motor, and superior/inferior parietal cortical regions, as well as regions of the caudate/putamen of the basal ganglia and the ventro-lateral thalamus. Importantly, within the cortical regions that were active for both complex movements, MVPA could accurately classify different patterns of activation for the sequential rhythm and sequential order tasks. In the basal ganglia, however, overlapping activation for the sequential rhythm and sequential order tasks, which was found in classic motor circuits of the putamen and ventro-lateral thalamus, could not be accurately differentiated by MVPA. Overall, our results highlight the convergent architecture of the motor system, where complex motor information that is spatially distributed in the cortex converges into a more compact representation in the basal ganglia.
PMCID: PMC4515550  PMID: 26283945
high-resolution fMRI; motor control; motor rhythm; motor order; multi-voxel pattern analysis; basal ganglia
10.  The increased risks of death and extra lengths of hospital and ICU stay from hospital-acquired bloodstream infections: a case–control study 
BMJ Open  2013;3(10):e003587.
Hospital-acquired bloodstream infections are known to increase the risk of death and prolong hospital stay, but precise estimates of these two important outcomes from well-designed studies are rare, particularly for non-intensive care unit (ICU) patients. We aimed to calculate accurate estimates, which are vital for estimating the economic costs of hospital-acquired bloodstream infections.
Case–control study.
9 Australian public hospitals.
All the patients were admitted between 2005 and 2010.
Primary and secondary outcome measures
Risk of death and extra length of hospital stay associated with nosocomial infection.
The greatest increase in the risk of death was for a bloodstream infection with methicillin-resistant Staphylococcus aureus (HR=4.6, 95% CI 2.7 to 7.6). This infection also had the longest extra length of stay to discharge in a standard bed (12.8 days, 95% CI 6.2 to 26.1 days). All the eight bloodstream infections increased the length of stay in the ICU, with longer stays for the patients who eventually died (mean increase 0.7–6.0 days) compared with those who were discharged (mean increase: 0.4–3.1 days). The three most common organisms associated with Gram-negative infection were Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumonia.
Bloodstream infections are associated with an increased risk of death and longer hospital stay. Avoiding infections could save lives and free up valuable bed days.
PMCID: PMC3816236  PMID: 24176795
Infectious Diseases; General Medicine (see Internal Medicine); Intensive & Critical Care
11.  Impact of the Genome on the Epigenome Is Manifested in DNA Methylation Patterns of Imprinted Regions in Monozygotic and Dizygotic Twins 
PLoS ONE  2011;6(10):e25590.
One of the best studied read-outs of epigenetic change is the differential expression of imprinted genes, controlled by differential methylation of imprinted control regions (ICRs). To address the impact of genotype on the epigenome, we performed a detailed study in 128 pairs of monozygotic (MZ) and 128 pairs of dizygotic (DZ) twins, interrogating the DNA methylation status of the ICRs of IGF2, H19, KCNQ1, GNAS and the non-imprinted gene RUNX1. While we found a similar overall pattern of methylation between MZ and DZ twins, we also observed a high degree of variability in individual CpG methylation levels, notably at the H19/IGF2 loci. A degree of methylation plasticity independent of the genome sequence was observed, with both local and regional CpG methylation changes, discordant between MZ and DZ individual pairs. However, concordant gains or losses of methylation, within individual twin pairs were more common in MZ than DZ twin pairs, indicating that de novo and/or maintenance methylation is influenced by the underlying DNA sequence. Specifically, for the first time we showed that the rs10732516 [A] polymorphism, located in a critical CTCF binding site in the H19 ICR locus, is strongly associated with increased hypermethylation of specific CpG sites in the maternal H19 allele. Together, our results highlight the impact of the genome on the epigenome and demonstrate that while DNA methylation states are tightly maintained between genetically identical and related individuals, there remains considerable epigenetic variation that may contribute to disease susceptibility.
PMCID: PMC3184992  PMID: 21991322
12.  Common variants in TMPRSS6 are associated with iron status and erythrocyte volume 
Nature genetics  2009;41(11):1173-1175.
We report a genome-wide association study to iron status. We identify an association of SNPs in TPMRSS6 to serum iron (rs855791, combined P = 1.5×10−20), transferrin saturation (combined P = 2.2×10−23), and erythrocyte mean cell volume (MCV, combined P = 1.1×10−10). We also find suggestive evidence of association with blood haemoglobin levels (combined P = 5.3×10−7). These findings demonstrate the involvement of TMPRSS6 in control of iron homeostasis and in normal erythropoiesis.
PMCID: PMC3135421  PMID: 19820699
13.  Genetic Linkage Findings for DSM-IV Nicotine Withdrawal in Two Populations 
Nicotine withdrawal (NW) is both an important contributor to difficulty quitting cigarettes and because of mood-related withdrawal symptoms a problem of particular relevance to psychiatry. Twin-studies suggest that genetic factors influence NW (heritability= 45%). Only one previous linkage study has published findings on NW (Swan et al., 2006; LOD=2.7; Chr. 6 at 159 cM). As part of an international consortium, genome-wide scans (using 381 autosomal microsatellite markers) and telephone diagnostic interviews were conducted on 289 Australian (AUS) and 161 Finnish (FIN, combined (COMB) N=450 families) families ascertained from twin registries through index-cases with a lifetime history of cigarette smoking. The statistical approach used an affected-sib pair design (at least two adult full siblings reported a history of DSM-IV NW) and conducted the linkage analyses using MERLIN. Linkage signals with LOD scores greater than 1.5 were found on two chromosomes: 6 (FIN: LOD= 1.93 at 75 cM) and 11 at two different locations (FIN: LOD= 3.55 at 17 cM, and AUS: LOD= 1.68 with a COMB: LOD= 2.30 at 123 cM). The multipoint LOD score of 3.55 on chromosome 11p15 in FIN met genomewide significance (p = .013 with 1000 simulations). At least four strong candidate genes lie within or near this peak on chromosome 11: DRD4, TPH, TH, and CHRNA10. Other studies have reported that chromosome 11 may harbor genes associated with various aspects of smoking behavior. This study adds to that literature by highlighting evidence for nicotine withdrawal.
PMCID: PMC2995916  PMID: 19180564
genetics; linkage; nicotine; withdrawal
14.  The perception of quinine taste intensity is associated with common genetic variants in a bitter receptor cluster on chromosome 12 
Human Molecular Genetics  2010;19(21):4278-4285.
The perceived taste intensities of quinine HCl, caffeine, sucrose octaacetate (SOA) and propylthiouracil (PROP) solutions were examined in 1457 twins and their siblings. Previous heritability modeling of these bitter stimuli indicated a common genetic factor for quinine, caffeine and SOA (22–28%), as well as separate specific genetic factors for PROP (72%) and quinine (15%). To identify the genes involved, we performed a genome-wide association study with the same sample as the modeling analysis, genotyped for approximately 610 000 single-nucleotide polymorphisms (SNPs). For caffeine and SOA, no SNP association reached a genome-wide statistical criterion. For PROP, the peak association was within TAS2R38 (rs713598, A49P, P = 1.6 × 10−104), which accounted for 45.9% of the trait variance. For quinine, the peak association was centered in a region that contains bitter receptor as well as salivary protein genes and explained 5.8% of the trait variance (TAS2R19, rs10772420, R299C, P = 1.8 × 10−15). We confirmed this association in a replication sample of twins of similar ancestry (P = 0.00001). The specific genetic factor for the perceived intensity of PROP was identified as the gene previously implicated in this trait (TAS2R38). For quinine, one or more bitter receptor or salivary proline-rich protein genes on chromosome 12 have alleles which affect its perception but tight linkage among very similar genes precludes the identification of a single causal genetic variant.
PMCID: PMC2951861  PMID: 20675712
15.  Five-Year Data and Prognostic Factor Analysis of Oxaliplatin and Irinotecan Combinations for Advanced Colorectal Cancer: N9741 
Journal of Clinical Oncology  2008;26(35):5721-5727.
In this report, we update survival (OS) and time-to-progression (TTP) data for the Intergroup trial N9741 after a median 5 years of follow-up by using risk-stratified and prognostic factor analyses to determine if treatment outcomes differ in specific patient subgroups.
Patients and Methods
A total of 1,691 patients were randomly assigned to one of seven fluorouracil-, oxaliplatin-, and irinotecan-containing regimens. OS and TTP were calculated by treatment arm and baseline risk group (on the basis of WBC, performance status, number of sites of disease, and alkaline phosphatase). Multivariate prognostic factor analysis was used to assess clinical factors for their relationships to OS, TTP, response, and toxicity by using Cox and logistic regression models.
The observed 5-year survival with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) of 9.8% was better than with irinotecan plus bolus fluorouracil and leucovorin (IFL; 3.7%; P = .04) or with bolus irinotecan/oxaliplatin (IROX; 5.1%; P = .128). OS and TTP were significantly longer for FOLFOX (20.2 months and 8.9 months, respectively) than for IFL (14.6 months and 6.1 months, respectively; P < .001 for both) or for IROX (17.3 months and 6.7 months, respectively; P < .001 for both). OS differed by risk group: 20.7 months for low risk, 17.4 months for intermediate risk, and 9.4 months for high risk (P < .001). FOLFOX treatment was superior in all risk groups and was the most powerful prognostic factor for OS, TTP, response rate, and toxicity.
The 9.8% 5-year OS in patients with metastatic colorectal cancer who were treated with first-line FOLFOX sets a new benchmark. Neither baseline risk group nor any prognostic factor examined was predictive of treatment-specific outcome. However, treatment efficacy and patient longevity varied as a function of risk group.
PMCID: PMC2645101  PMID: 19001325
16.  Protocol for the Osteoporosis Choice trial. A pilot randomized trial of a decision aid in primary care practice 
Trials  2009;10:113.
Bisphosphonates can reduce fracture risk in patients with osteoporosis, but many at-risk patients do not start or adhere to these medications. The aims of this study are to: (1) preliminarily evaluate the effect of an individualized 10-year osteoporotic fracture risk calculator and decision aid (OSTEOPOROSIS CHOICE) for postmenopausal women at risk for osteoporotic fractures; and (2) assess the feasibility and validity (i.e., absence of contamination) of patient-level randomization (vs. cluster randomization) in pilot trials of decision aid efficacy.
This is a protocol for a parallel, 2-arm, randomized trial to compare an intervention group receiving OSTEOPOROSIS CHOICE to a control group receiving usual primary care. Postmenopausal women with bone mineral density T-scores of <-1.0, not receiving bisphosphonate therapy, and receiving care at participating primary care practices in and around Rochester, Minnesota, USA will be eligible to participate in the trial. We will measure the effect of OSTEOPOROSIS CHOICE on five outcomes: (a) patient knowledge regarding osteoporosis risk factors and treatment; (b) quality of the decision-making process for both the patient and clinician; (c) patient and clinician acceptability and satisfaction with the decision aid; (d) rate of bisphosphonate use and adherence, and (e) trial processes (e.g., ability to recruit participants, collect patient outcomes). To capture these outcomes, we will use patient and clinician surveys following each visit and video recordings of the clinical encounters. These video recordings will also allow us to determine the extent to which clinicians previously exposed to the decision aid were able to recreate elements of the decision aid with control patients (i.e., contamination). Pharmacy prescription profiles and follow-up phone interviews will assess medication start and adherence at 6 months.
This pilot trial will provide evidence of feasibility, validity of patient randomization, and preliminary efficacy of a novel approach -- decision aids -- to improving medication adherence for postmenopausal women at risk of osteoporotic fractures. The results will inform the design of a larger trial that could provide more precise estimates of the efficacy of the decision aid.
Trial registration
Clinical Identifier: NCT00578981
PMCID: PMC2796658  PMID: 20003299
17.  Common sequence variants on 20q11.22 confer melanoma susceptibility 
Nature genetics  2008;40(7):838-840.
We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totalling 2019 cases and 2105 controls. Using pooling we identified a novel melanoma risk locus on chromosome 20 (rs910873, rs1885120), with replication in two further samples (combined P <1 × 10-15). The odds ratio is 1.75 (1.53, 2.01), with evidence for stronger association in early onset cases.
PMCID: PMC2755512  PMID: 18488026
18.  Induction of a Chronic Disease State in Patients With Smoldering or Indolent Multiple Myeloma by Targeting Interleukin 1β-Induced Interleukin 6 Production and the Myeloma Proliferative Component 
Mayo Clinic Proceedings  2009;84(2):114-122.
OBJECTIVE: To conduct in vitro studies as well as a phase 2 clinical trial in patients with smoldering or indolent multiple myeloma to determine if interleukin 1 (IL-1) inhibitors can delay or prevent active myeloma.
PATIENTS AND METHODS: Stromal cells were cocultured with IL-1β-expressing myeloma cells in the presence of dexamethasone, IL-1 receptor antagonist (IL-1Ra), or both. Levels of interleukin 6 (IL-6) and of apoptosis were also quantified. Between November 19, 2002, and May 24, 2007, 47 patients were enrolled in the study and subsequently treated with IL-1Ra. In 25 (53%) of the 47 study patients, low-dose dexamethasone (20 mg/wk) was added. The primary end point was progression-free survival (PFS).
RESULTS: In vitro, IL-1Ra was superior to dexamethasone at inhibiting IL-6 production; maximal IL-6 inhibition and apoptosis induction were achieved by addition of both IL-1Ra and dexamethasone. In the clinical trial, 3 patients achieved a minor response to IL-1Ra alone; 5 patients achieved a partial response and 4 patients a minor response after addition of dexamethasone. Seven patients showed a decrease in the plasma cell labeling index that paralleled a decrease in high-sensitivity C-reactive protein (hs-CRP) levels. The median overall PFS was 37.5 months. The median PFS for patients without (n=12) or with (n=35) a greater than 15% decrease in 6-month vs baseline hs-CRP levels was 6 months and more than 3 years, respectively (P=.002). Disease stability was maintained in 8 patients who received therapy for more than 4 years.
CONCLUSION: In patients with smoldering or indolent multiple myeloma who were at risk of progression to active myeloma, treatment with IL-1 inhibitors decreased the myeloma proliferative rate and hs-CRP levels in those who responded, leading to a chronic disease state and an improved PFS.
Trial Registration: identifier: NCT00635154
In patients with smoldering or indolent multiple myeloma at risk of progression to active myeloma, treatment with interleukin 1 inhibitors decreased the myeloma proliferative rate and high-sensitivity C-reactive protein levels in those who responded, leading to a chronic disease state and an improved progression-free survival.
PMCID: PMC2664581  PMID: 19181644
19.  Immunoglobulin diversity gene usage predicts unfavorable outcome in a subset of chronic lymphocytic leukemia patients 
Survival of patients with B cell chronic lymphocytic leukemia (B-CLL) can be predicted by analysis of mutations in the immunoglobulin heavy chain variable gene (IGHV). Patients without mutations (unmutated [UM]) are at greater risk for disease progression and death than patients with mutations (M). Despite this broad prognostic difference, there remains wide intragroup variation in the clinical outcome of UM patients, especially those with low/intermediate Rai risk disease. We evaluated UM B-CLL patients with low/intermediate Rai risk to determine the relationship between IGHV, IGH diversity (IGHD), and IGH joining (IGHJ) gene usage and time to treatment (TTT). Irrespective of IGHV usage, UM patients whose B-CLL cells expressed the IGHD3-3 gene had a significantly shorter TTT than other UM B-CLL patients, and specifically, use of the IGHD3-3 gene in reading frame 2 (RF2) predicted shorter TTT. As expected, Rai risk was the best single prognostic factor for TTT; however, IGHD usage was also a significant variable for TTT. Therefore, both IGHD gene and IGHD RF usage have prognostic relevance in UM B-CLL patients with low/intermediate Rai risk disease. In addition, these data support the concept that antigen-driven selection of specific Ig receptors plays a role in the clinical course of B-CLL.
PMCID: PMC2117767  PMID: 18064298
20.  Evaluation of multiple displacement amplification in a 5 cM STR genome-wide scan 
Nucleic Acids Research  2005;33(13):e119.
Multiple displacement amplification (MDA) has emerged as a promising new method of whole genome amplification (WGA) with the potential to generate virtually unlimited genome-equivalent DNA from only a small amount of seed DNA. To date, genome-wide high marker density assessments of MDA–DNA have focussed mainly upon suitability for single nucleotide polymorphism (SNP) genotyping applications. Suitability for short tandem repeat (STR) genotyping has not been investigated in great detail, despite their inherent instability during DNA replication, and the obvious challenge that this presents to WGA techniques. Here, we aimed to assess the applicability of MDA in STR genotyping by conducting a genome-wide scan of 768 STR markers for MDAs of 15 high quality genomic DNAs. We found that MDA genotyping call and accuracy rates were only marginally lower than for genomic DNA. Pooling of three replicate MDAs resulted in a small increase in both call rate and genotyping accuracy. We identified 34 STRs (4.4% of total markers) of which five essentially failed with MDA samples, and 29 of which showed elevated genotyping failures/discrepancies in the MDAs. We emphasise the importance of DNA and MDA quality checks, and the use of appropriate controls to identify problematic STR markers.
PMCID: PMC1182175  PMID: 16055919

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